Vignesh P, Mondal S, Aggarwal R
… +17 more, Siniah S, Loganathan SK, Bhattarai D, Das J, Goel S, Sharma K, Kaur H, Sekar A, Dhaliwal M, Sharma S, Pilania RK, Jindal AK, Suri D, Gupta K, Rudramurthy SM, Rawat A, Singh S
J Clin Immunol
· 2025 Nov · PMID 41201521
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Fungal infections contribute to a significant disease burden in patients with chronic granulomatous disease (CGD). While the presentation may differ depending on genotype and environmental exposure to fungus, associated...Fungal infections contribute to a significant disease burden in patients with chronic granulomatous disease (CGD). While the presentation may differ depending on genotype and environmental exposure to fungus, associated mortality rates are universally high. This is a retrospective study wherein medical records of patients diagnosed with CGD from 1994 to 2022 at our center in North India were reviewed. We categorized patients into 2 groups: patients with proven invasive fungal infection and patients with probable invasive fungal infections. We analyzed demographic details, clinical details, and the overall outcome of these patients. We identified 40 patients (40.4%) with fungal infections in our cohort of 99 patients with CGD. Twenty-one patients had proven invasive fungal infection, and 19 had probable invasive fungal infection. Pneumonia was the most common presentation in our cohort (n = 35; 87.5%). Two patients had isolated osteomyelitis, 1 had brain abscess, and 2 had candidemia. Aspergillus sp. was isolated most frequently (n = 27), followed by Candida sp. (n = 5), Mucorales sp. (n = 2), Paecilomyces sp. (n = 1) and Fusarium dimerum (n = 1). Aspergillus fumigatus (n = 11) was the most identified species of Aspergillus. Eleven patients had bacterial co-infection. Twenty-one patients (52.5%) died in this cohort. Risk factors for mortality identified are X-linked CGD (p = 0.027), bacterial coinfection (p = 0.003) and infection in infancy (p = 0.045). Aspergillus sp. is the most common offending fungus, and pneumonia is the most common manifestation of fungal infection in our patients with CGD. Infants, males, and patients with bacterial coinfection should be treated more aggressively amongst patients with CGD with fungal infection.
Lefevre L, Paccoud O, Neven B
… +32 more, Bougnoux ME, Alligon M, Bruneau J, Fischer A, Moshous D, Bustamante J, Picard C, Poiree S, Guery R, Castelle M, Suarez F, Marcais A, Cheminant M, Rouzaud C, Hermoso DG, Salvator H, Catherinot E, Pilmis B, Luca L, Brion JP, Revest M, Gandemer V, Lelievre L, Alvarez M, Conrad A, Fouyssac F, Gaud C, Blumental S, Blanche S, Lortholary O, Mahlaoui N, Lanternier F
J Clin Immunol
· 2025 Nov · PMID 41193884
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BACKGROUND: Non-Aspergillus invasive fungal infections (NAFI) are increasingly reported in patients with Chronic Granulomatous Disease (CGD), but precise clinical descriptions remain scarce. OBJECTIVE AND METHODS: We con...BACKGROUND: Non-Aspergillus invasive fungal infections (NAFI) are increasingly reported in patients with Chronic Granulomatous Disease (CGD), but precise clinical descriptions remain scarce. OBJECTIVE AND METHODS: We conducted a retrospective analysis of NAFI cases among CGD patients in the French National Registry of Primary Immunodeficiencies (CEREDIH) and in a comprehensive literature review. RESULTS: We identified 16 proven NAFI (9 molds, 6 yeasts and 1 Pneumocystis) among 263 CGD patients from CEREDIH and included an additional 106 probable/proven NAFI from a literature review (75 molds, 29 yeasts, 1 Pneumocystis, 1 dimorphic). Mold NAFI occurred at a median age of 17 years [IQR 9-23], and were mostly located to the lungs (79%, 65/82). Mold NAFI were breakthrough in 59% of patients (35/59), and 24% were receiving immunosuppressive treatments (13/54, mostly high-dose corticosteroids, n = 11). Lung surgical biopsies yielded the highest diagnostic rate (39/39) compared to less invasive methods (BAL 8/18 and transthoracic punctures 8/12). Nine patients with mold NAFI, including 3 refractory cases, were cured after Hematopoietic Stem Cell Transplantation (HSCT). Overall mortality for mold NAFI was 25% (20/81). Yeast infections occurred at a median age of 5 years [IQR 0-13], and 36% were receiving immunosuppressive treatments (5/14, mostly anti-TNF agents, n = 4). Infections were frequently located to lymph nodes or lungs, and 64% (21/33) were disseminated. Two yeast NAFI were cured after HSCT. Mortality was 26% (7/27). CONCLUSION: NAFI in CGD patients are frequently severe, often occur despite prophylaxis and under additional immunosuppression, commonly require invasive procedures for diagnosis, and may be effectively managed with HSCT.
Pinc Z, Kundrat D, Kaisrlikova M
… +15 more, Hrustincova A, Vanikova S, Trsova I, Vesela J, Vostry M, Pejsova B, Ransdorfova S, Slamova L, Prochazka T, Lysak D, Jonasova A, Markova MS, Cermak J, Belickova M, Votavova H
J Clin Immunol
· 2025 Nov · PMID 41188636
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PURPOSE: Bone marrow failure (BMF) in idiopathic aplastic anemia (AA) and hypoplastic myelodysplastic neoplasms (MDS-h) results from the destruction of hematopoietic progenitors by autoreactive T cells; however, the mole...PURPOSE: Bone marrow failure (BMF) in idiopathic aplastic anemia (AA) and hypoplastic myelodysplastic neoplasms (MDS-h) results from the destruction of hematopoietic progenitors by autoreactive T cells; however, the molecular events driving the pathogenesis of these disorders remain unclear. We therefore applied whole-exome sequencing (WES) in AA and MDS-h patients to identify acquired and inherited gene variants presumed to have functional consequences for BMF. We also used transcriptome profiling to investigate the molecular mechanisms underlying the aberrant T cell response. METHODS: WES was performed on DNA from 42 patients at diagnosis. Transcriptome profiling of CD3⁺ cells was conducted in 21 patients and 10 healthy donors. Peripheral blood cell populations were analyzed by flow cytometry. RESULTS: Pathogenic/likely pathogenic (P/LP) somatic gene variants were detected in 79% of patients and were functionally associated with BMF-relevant processes such as antigen processing/presentation, T cell-mediated immunity, and DNA repair. P/LP germline gene variants were found in all patients, almost half of whom harbored variants associated with inborn errors of immunity. Patient T cells displayed expression signatures of increased inflammation, apoptosis, hypoxia response, and decreased oxidative phosphorylation. Dysregulated long noncoding RNAs were predicted to primarily regulate the differentiation of T helper 17 cells. Patients also showed significantly lower frequencies of immature progenitors and natural killer cells compared with controls. CONCLUSION: Patients with idiopathic AA and MDS-h carried multiple germline immune-related gene variants that may increase susceptibility to immune-mediated BMF. Furthermore, patient T cells exhibited altered energy metabolism, which may represent a therapeutic target for modulating immune responses in autoimmune diseases.
Yaz I, Oskay Halacli S, Ipsir C
… +14 more, Ulum B, Soyak Aytekin E, Bildik HN, Ocak M, Avci H, Okur FV, Hizarcioglu Gulsen H, Demir H, Metin A, Ozon A, Kuskonmaz B, Tezcan I, Esenboga S, Cagdas D
J Clin Immunol
· 2025 Oct · PMID 41117878
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BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX) syndrome caused by FOXP3 mutations is rare. FOXP3 is a transcription factor required for the regulatory T cell (Treg) development/func...BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX) syndrome caused by FOXP3 mutations is rare. FOXP3 is a transcription factor required for the regulatory T cell (Treg) development/function. AIM: We aimed to characterize the clinical, immunologic, and genetic features of a single-center cohort of IPEX syndrome. PATIENTS AND METHODS: We present the clinical/immunological/genetic features of 12 patients with IPEX syndrome. We used whole exome and Sanger sequencing for the diagnosis/familial segregation. We performed immunophenotyping and measured Treg percentage and FOXP3 expression in peripheral blood by flow cytometric analysis. RESULTS: Median age at diagnosis was 2.5 years (range: 0.3-22 years). Common clinical manifestations were infections (n = 9, 75%), allergies (n = 8, 67%), autoimmunity (n = 7, 58%), enteropathy (n = 7, 58%), and lymphoproliferation (n = 3, 25%). Atypical initial presentations included class IV lupus nephritis, a SCID-like immunophenotype (CD3 T cells: 4% [100/µL]; CD4 T cells: 3%, CD8 T cells: 1%, CD19 B cells: 81%, CD16/56 NK cells: 13%), and isolated hypogammaglobulinemia persisting for years during follow-up. At the time of diagnosis, three (25%) patients had leukopenia, six (50%) had lymphopenia and two (17%) had neutropenia. Eosinophilia was observed in 42% of patients (25% mild, 17% moderate). Six different variants in FOXP3 were characterized in 12 patients from nine unrelated families. Four (33%) patients underwent hematopoietic stem cell transplantation (HSCT). Overall, three (25%) patients died due to infections. One patient died due to HSCT-related catheter complications, one patient died in an accident. Among the transplanted patients, two are alive and well. Among the non-transplanted patients, five are alive and are being followed up at our center. Treg (CD4CD127CD25Foxp3) percentage was low in eight patients compared to healthy controls (p < 0.001). FOXP3 expression was low in all the patients compared to healthy controls. CONCLUSION: Atypical presentations make the diagnosis of IPEX syndrome challenging. This study expands the current knowledge of IPEX syndrome by describing a single-center cohort with certain atypical manifestations and by confirming previously reported rare phenotypes. Elucidating the genetic basis of immunodeficiency diseases contributes to improving diagnostic approaches and patient management.
Durán V, Nikolouli E, Chatterjee S
… +17 more, Costa B, Pavlou A, Ziegler A, Becker J, Baumann K, Bruhn M, Haake K, Hashtchin AR, Gensch I, Korte A, Behrens YL, Zhang SY, Casanova JL, Bär C, Lachmann N, Thum T, Kalinke U
J Clin Immunol
· 2025 Oct · PMID 41117873
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The cellular basis of COVID-19 severity in patients with deficiencies in type I IFN immunity remains unclear. In this study, we differentiated cardiomyocytes and macrophages from IFNAR1 competent (IFNAR1) and deficient (...The cellular basis of COVID-19 severity in patients with deficiencies in type I IFN immunity remains unclear. In this study, we differentiated cardiomyocytes and macrophages from IFNAR1 competent (IFNAR1) and deficient (IFNAR1) induced pluripotent stem cells (iPSCs), and analyzed virus replication and cytokine production after exposure to SARS-CoV-2. Cardiomyocytes expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) and showed abundant SARS-CoV-2 replication, which was higher in IFNAR1 than IFNAR1 cells. Treatment with exogenous IFNα mitigated infection in IFNAR1, but not in IFNAR1 cardiomyocytes. In contrast, macrophages did not express ACE2 and did not support SARS-CoV-2 replication, but produced pro-inflammatory cytokines upon virus exposure, which was impaired in IFNAR1 macrophages. In conclusion, type I IFNs decrease SARS-CoV-2 replication in human iPSC-derived cardiomyocytes, while they increase cytokine responses of macrophages.
Edwards ESJ, Chatelier J, Snell GI
… +5 more, Seo GH, Khang R, O'Hehir RE, Bosco JJ, van Zelm MC
J Clin Immunol
· 2025 Oct · PMID 41114848
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BACKGROUND: Inborn errors of immunity (IEI) affecting B-cell receptor signaling cause predominantly antibody deficiency (PAD) with varying degrees of severity. Recently, four heterozygous variants in SYK were reported to...BACKGROUND: Inborn errors of immunity (IEI) affecting B-cell receptor signaling cause predominantly antibody deficiency (PAD) with varying degrees of severity. Recently, four heterozygous variants in SYK were reported to cause hypogammaglobulinemia, multiorgan inflammatory disease and diffuse large B-cell lymphoma. OBJECTIVE: We aimed to unravel the genetic and functional cause of PAD in a 43-year-old female presenting with hypogammaglobulinemia, congenital heart disease and pulmonary hypertension requiring lung transplantation. METHODS: Patient gDNA was subjected to whole-exome and Sanger sequencing. Blood B- and T-cell subsets, as well as tonic and antigen-receptor induced expression levels of phosphorylated-SYK, phosphorylated-ribosomal S6 and phosphorylated p38 were evaluated by flow cytometry. RESULTS: A novel heterozygous missense SYK variant was identified, mutating a residue in the protein kinase domain (c.1769G > A; p.R590Q), which is highly conserved across vertebrates. While total B- and T-cell numbers were within the normal range, the patient had reduced unswitched and class-switched memory B-cell numbers. Resting B cells from the patient demonstrated enhanced autophosphorylation of SYK, and tonic and ligand-induced phospho-S6 levels. Spontaneous SYK autophosphorylation, S6 and p38 phosphorylation were recapitulated in a pre-clinical cell model, i.e. expression of the SYK R590Q variant in HEK293T cells. CONCLUSIONS: We identified a novel gain-of-function variant in SYK to underlie hypogammaglobulinemia and atypical autoinflammatory disease. Flowcytometric screening for phospho-S6 in lymphocytes of IEI patients can guide genetic diagnosis of B-cell signaling abnormalities.
Mechernene B, Lehours P, Rivière E
… +15 more, Gensous N, Tinévez C, Duffau P, Blaison F, Prot-Leurent C, Pires T, Greib C, Zannese T, Dubois M, Bénéjat L, Ducournau A, Aptel J, Jehanne Q, Viallard JF, Lazaro E
J Clin Immunol
· 2025 Oct · PMID 41099909
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Hypogammaglobulinemia (HG) predisposes patients to gastrointestinal Campylobacter infections. This prospective study determined the prevalence of Campylobacter in stool samples from patients with immunoglobulin (Ig)-subs...Hypogammaglobulinemia (HG) predisposes patients to gastrointestinal Campylobacter infections. This prospective study determined the prevalence of Campylobacter in stool samples from patients with immunoglobulin (Ig)-substituted HG at Bordeaux University Hospital. 73 patients (42 women, median age: 61) receiving Ig substitution therapy were enrolled from July 2022 to July 2024. Stool samples were analysed with culture, PCR, faecal calprotectin levels, and immune profiles were also assessed. A second stool sample was collected from 38 patients after 6-12 months, totalling 111 samples. 53 patients had primary HG (32 common variable immunodeficiency, 7 IgG subclass deficiencies, 4 Bruton's agammaglobulinemias) and 20 had secondary HG (7 drug-induced, 8 lymphoid hemopathy-related, 5 mixed). Campylobacter were detected in 11 patients (15.1%), with species identified as Campylobacter jejuni, Campylobacter coli, and Aliarcobacter butzleri. Diarrhea was reported in 42% of Campylobacter-positive patients versus 15% of negative patients. Campylobacter-positive patients exhibited higher median faecal calprotectin levels (255 µg/g vs. 52 µg/g). Among positive patients, 44% (versus 34% in negative patients) had non-infectious complications such as immune complications. Mean residual IgG levels were similar between groups, although IgA and IgM were lower in Campylobacter-positive patients (0 vs. 0.36 g/L and 0.17 vs. 0.40 g/L, respectively). The mean CD4/CD8 ratio was also lower in the positive group (1.71 ± 0.85 vs. 2.06 ± 1.18). This study reveals a high prevalence of Campylobacter in HG patients despite receiving Ig therapy. Elevated faecal levels of calprotectin in symptomatic patients suggests active infection. Screening for Campylobacter should be considered in HG patients presenting with digestive symptoms.
Aliyeva G, Bajin IY, Orhan D
… +3 more, Kutluk T, Kösemehmetoğlu K, Cagdas D
J Clin Immunol
· 2025 Oct · PMID 41099879
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BACKGROUND: Primary immunodeficiency disease (PID)/Inborn Errors of Immunity (IEI) with T-cell dysfunction is well-known for susceptibility to opportunistic/viral infections. Epstein–Barr virus-positive smooth muscle tum...BACKGROUND: Primary immunodeficiency disease (PID)/Inborn Errors of Immunity (IEI) with T-cell dysfunction is well-known for susceptibility to opportunistic/viral infections. Epstein–Barr virus-positive smooth muscle tumor (EBV-SMT) is a rare entity primarily seen in the setting of immunodeficiency, such as transplantation, HIV/AIDS, and IEI. AIM: This study aimed to characterize patients’ clinical/immunologic/genetic features with EBV-SMT and assess their association with IEI. METHODS: We reviewed the medical records of patients with EBV-SMT in an outpatient immunology clinic and analyzed a total of 33 patients, including 24 identified from the literature. RESULTS: The study included nine patients (male/ female = 6/3). The median ages at the onset of symptoms, clinical diagnosis of PID, genetic diagnosis, and EBV-SMT diagnosis were 12 months (1–84 months), 6 years (2–15 years), 10 years (6–18 years), and 10 years (4–18 years), respectively. The parental consanguinity ratio was 7/9(78%). Four patients had combined immunodeficiency. Five out of nine patients (56%) received a genetic IEI diagnosis: JAK3 deficiency (n = 1), STAT1 GOF (n = 1), CARMIL2 deficiency (n = 1), DOCK8 deficiency (n = 1), and ITK deficiency (n = 1). Recurrent infections (100%), chronic diarrhea/colitis (78%), organomegaly (67%), and lymphadenopathy (56%) were prevalent among the patients. Six patients exhibited leiomyoma-like morphology, while three had leiomyosarcoma-like morphology. Five out of nine patients (55%) died, two of whom succumbed due to the complications of hematopoietic stem cell transplantation. CONCLUSION: EBV-SMT may suggest an underlying immunodeficiency. Since the mortality is high, early genetic diagnosis of IEI, monitoring the patients with IEI for chronic EBV and cancer, and an individualized therapeutic approach will minimize complications.
Blom M, Duintjer AJ, Jamee M
… +36 more, de Gier M, Bloomfield M, Klocperk A, Kralickova P, Karaca NE, Boyarchuk O, Čižnár P, Jeseňák M, Sharapova S, Skopovets E, Gonzalez-Granado LI, Palmeri S, Volpi S, Nalda AM, Tello SR, Soler-Palacín P, Abolhassani H, Pulvirenti F, Cinicola B, Wintergerst U, de Bree GJ, van den Berg JM, Leavis HL, Vermont C, Dalm VASH, van Aerde K, Henriet S, Jolink H, Potjewijd J, Lankester A, Mukherjee CR, Berghuis D, Pac M, Shillitoe BMJ, Gennery AR, van der Burg M
J Clin Immunol
· 2025 Oct · PMID 41065887
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J Clin Immunol
· 2025 Oct · PMID 41032161
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INTRODUCTION: Specific determinants of target-organ damage in autoimmune diseases are complex and multifactorial, several genetic and environmental factors are recognized but mostly remain unknown. Immunotherapy with "ch...INTRODUCTION: Specific determinants of target-organ damage in autoimmune diseases are complex and multifactorial, several genetic and environmental factors are recognized but mostly remain unknown. Immunotherapy with "check-point inhibitors" (CPI) is complicated by immune related adverse events (IRAE), occurring in a large fraction of patients, with organ-specific inflammation of immunologic aetiology. We hypothesized that such IRAE are associated to regulatory T cell (Treg) dysfunction. To start testing this hypothesis, we have now compared organ targets of CPI-induced IRAE with those described in IPEX (Immune dysregulation polyendocrinopathy enteropathy X-linked) patients carriers of deleterious mutations in the Foxp3 gene leading to deficient/absent Treg. METHOD: We compared the frequency of autoimmune diseases (AID) in three groups of conditions: CPI-induced IRAE, IPEX patients, and the General Population (GP) through a PubMed search from 01/01/1998 to 31/05/2024. For each group, and each autoimmune disease, the highest reported frequency was selected, listed in reference to CPI-IRAE and classified from the highest to lowest prevalence. Identified were enteropathy, rash (eczema or other dermatitis), transaminitis/hepatitis, hypothyroidism, increased lipase/exocrine pancreatitis, arthralgia/inflammatory arthritis, hypophysitis, adrenal insufficiency, type 1 diabetes mellitus, haemolytic anaemia, Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis. RESULTS: While dermatitis and thyroid disease are also the most frequent AID in the GP, the latter, together with enteropathy, hepatitis, and adrenal insufficiency are much more frequent in CPI-IRAE and IPEX. Of note, the most frequent systemic AID in the GP such as de novo Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis are extremely rare in CPI-IRAE (few case reports) and not described in IPEX. CONCLUSION: Our finding provides further evidence for the possibility that the functional inhibition/inactivation of Treg is a plausible contributing mechanism in the physiopathology of CPI-IRAE.
J Clin Immunol
· 2025 Sep · PMID 41026346
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BACKGROUND: Caspase-8 enzyme deficiency (CED) is a rare autosomal recessive inborn error of immunity with autoimmune lymphoproliferative syndromes (ALPS), deficient extrinsic apoptosis and hyperactivation of the mammalia...BACKGROUND: Caspase-8 enzyme deficiency (CED) is a rare autosomal recessive inborn error of immunity with autoimmune lymphoproliferative syndromes (ALPS), deficient extrinsic apoptosis and hyperactivation of the mammalian target of rapamycin (mTOR) pathway. METHODS: Features of our patient with early onset chronic inflammatory demyelinating polyneuropathy (CIDP) are presented in detail. We report features of ALPS due to CED (ALPS-CED) in 6 patients in previous literature and our patient with the homozygous hotspot mutation, c.793 C > T in the CASP8 gene, and demonstrate that such mutation is a novel cause of CIDP. RESULTS: Our patient fits the spectrum of genetic disorders causing ALPS with dysregulation of the mTOR pathway. Autoimmune lymphoproliferative syndrome with FAS mutations (ALPS-FAS) is also associated with hyperactivation of the mTOR pathway but hematologic symptoms are more severe than ALPS-CED. Both ALPS-FAS and ALPS-CED lead to autoimmunity and improve with use of mTOR inhibitors. ALPS-FAS is characterized by the elevation of alpha beta-double negative T-cells (DNT) and hypergammaglobulinemia, while such features are not prominent in ALPS-CED. Patients with ALPS-CED not only suffer from ALPS but also present with an immune deficiency and a chronic inflammatory state both related to non-apoptotic functions of caspase-8. CONCLUSIONS: Both ALPS-FAS and ALPS-CED are characterized by deficient extrinsic apoptosis and dysregulation of the mTOR pathway. Compared to ALPS-FAS, the phenotype of ALPS-CED is more complex due to a more diffuse dysfunction of the non-apoptotic pathways. To our knowledge, early onset CIDP in a patient with homozygous hotspot mutation, c.793 C > T in CASP8, has not been reported previously.
J Clin Immunol
· 2025 Sep · PMID 41026334
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OBJECTIVE: Mutations in the HOIP gene, encoding Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1) interacting protein, a key component of the linear ubiquitination chain assembly complex (LUBAC), affect the activation of th...OBJECTIVE: Mutations in the HOIP gene, encoding Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1) interacting protein, a key component of the linear ubiquitination chain assembly complex (LUBAC), affect the activation of the NF-κB pathway and result in autoinflammation and immunodeficiency. To date, only three patients with HOIP mutations have been reported in the English literature. This study aimed to identify the genetic cause in a 1-year-6-month-old boy with early-onset autoinflammation and immunodeficiency. METHODS: Clinical manifestations and immunological phenotypes were assessed in a Chinese patient with novel compound heterozygous mutations in HOIP. Swiss-PdbViewer was used to predict the pathogenicity of the mutations. HOIP and LUBAC protein levels were evaluated by western blot. Immunological phenotypes and intracellular NF-κB phosphorylation in T and B cells were analyzed by flow cytometry, and the interferon (IFN) signature was assessed using quantitative reverse transcription PCR (RT-qPCR). RESULTS: The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations. Targeted gene sequencing identified novel compound heterozygous mutations in HOIP (c.1654 C > T, p.Gln552Ter; c.3038 A > C, p.His1013Pro). These mutations significantly reduced HOIP and LUBAC protein expression and altered the HOIP protein structure. Immunophenotyping revealed a reduction in CD8 + T cells, central memory (CD8 CM) and effector memory (CD8 EM) T cells, and CD4 + T cells. Subset analysis of CD4 + T cells showed decreased T follicular helper cells (Tfh) and increased IL-17-producing T helper (Th17) cells. The patient also exhibited a higher percentage of naïve B cells and a lower percentage of memory B cells, alongside impaired NF-κB phosphorylation in T and B cells upon LPS stimulation. The expression of the patient's interferon-stimulated gene (ISG) was markedly higher than that of healthy controls. CONCLUSION: HOIP mutations may lead to multiple immune abnormalities, impaired NF-κB activation, and activation of the type I interferon pathway. These findings highlight the diversity of HOIP mutations and expand the clinical spectrum of associated diseases.
Xiang Y, Sun S, Wang H
… +8 more, Lo CC, Wu J, Lei WT, Li F, Liu X, Dang N, Ku CL, Guo J
J Clin Immunol
· 2025 Sep · PMID 41026300
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OBJECTIVE: Germline heterozygous gain-of-function (GOF) mutations in STAT1 impair IL-17-mediated immunity, resulting in carriers' susceptibility to chronic mucocutaneous candidiasis (CMC). JAK inhibitors have shown thera...OBJECTIVE: Germline heterozygous gain-of-function (GOF) mutations in STAT1 impair IL-17-mediated immunity, resulting in carriers' susceptibility to chronic mucocutaneous candidiasis (CMC). JAK inhibitors have shown therapeutic effectiveness in patients with STAT1-GOF mutations. METHODS: The mutation was detected using whole-exome sequencing (WES) and confirmed by Sanger sequencing. The functional impact of the mutation was verified by luciferase reporter assay. The phosphorylation level of STAT1 in patient cells, the phenotyping of leukocyte subtypes, and serum cytokine levels were determined by flow cytometry. RESULTS: The patient with CMC harbors a heterozygous missense mutation in STAT1 (c.1078G > C, p.V360L). This mutation was functionally validated as a GOF mutation based on functional analysis of the variant and enhanced phosphorylation upon IFN-γ stimulation in the patient's cells. Additionally, the patient demonstrated a decreased proportion of CD4 + T cells, NK cells, and Th17 cells. Flow cytometry analysis revealed a significant decrease in the expression of IL-17 A in CD4 + T cells from the patient. Serological test results showed that the patient's IgM level was decreased, while the levels of IL-2, IL-5, IL-6 and TNF-α were elevated. Topical application of ruxolitinib demonstrated therapeutic efficacy. CONCLUSIONS: The present study reports a pediatric patient with CMC who carries a novel GOF mutation in STAT1. This mutation may impair IL-17 immunity, which could potentially increase the patient's susceptibility to CMC. However, further research is needed to elucidate the underlying mechanism. Although ruxolitinib shows potential as a therapeutic option for CMC, its clinical efficacy requires further validation through experimental studies and long-term patient follow-up.
Liao YX, Xia L, Liu P
… +16 more, Li XH, Liu LP, Xu L, Tian D, Shi DL, Guo XM, Mei X, Okada S, Liu YB, Wang FF, Wang XC, Zhao C, Fan XH, Sun JQ, Liu TF, Ling Y
J Clin Immunol
· 2025 Sep · PMID 41026270
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BACKGROUND: The CYBB gene encodes the gp91-phox protein, a critical component of the NADPH oxidase complex involved in pathogen clearance. Mutations in CYBB are associated with chronic granulomatous disease (CGD), leadin...BACKGROUND: The CYBB gene encodes the gp91-phox protein, a critical component of the NADPH oxidase complex involved in pathogen clearance. Mutations in CYBB are associated with chronic granulomatous disease (CGD), leading to recurrent bacterial infections. OBJECTIVE: To understand the genetic causes of Chinese CGD patients. METHODS: Exome sequencing was used to identify mutations in CGD patients' PBMCs, confirmed by Sanger sequencing. Neutrophil respiratory burst capacity was analyzed to correlate with clinical treatment efficacy. RESULTS: We identified five CYBB mutations in six CGD patients from five unrelated Chinese families, including two novel mutations (c.1507A > G:p.T503A, c.1587_1605del:p.529_535del), two rare mutations without functional characterization (c.43A > G:p.I15V, c.125C > A:p.T42K), and one recently reported in a different ethnicity (c.252G > T:p.A84A). Our analysis revealed that these mutations had varying effects on CYBB expression, demonstrating that the synonymous c.252G > T mutation is indeed a splicing mutation, resulting in exon 3 deletion and minimal protein expression. Neutrophils from all patients exhibited defective mitogen-stimulated respiratory bursts. However, only neutrophils with the I15V mutation responded to interferon-γ (IFN-γ) treatment, significantly improving the respiratory capacity defect. Consistent with this, the patient with the I15V mutation showed clinical improvement after two weeks of IFN-γ and anti-bacterial co-treatment. CONCLUSION: Our findings underscore the diverse effects of CYBB mutations on protein expression and function. More importantly, they suggest that assessing the IFN-γ-mediated potentiation of respiratory burst response in patient's neutrophils is an effective way to predict the therapeutic efficacy of IFN-γ in treating CGD cases, particularly those with non-tuberculous mycobacteria (NTM) and Mycobacterium tuberculosis (TB).
von Bornemann Fløe L, Dyrmose KO, Sørensen CD
… +11 more, Nørgaard M, Pedersen FKU, Vad-Nielsen J, Knudsen M, Christiansen M, Bill M, Rasch MNB, Hauge EM, Troldborg A, Staunstrup NH, Bernth Jensen JM
J Clin Immunol
· 2025 Sep · PMID 41026267
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VEXAS syndrome is an adult-onset autoinflammatory disorder caused by somatic UBA1 variants, but there are no standardized criteria for genetic testing or diagnostics. This study compared Sanger sequencing and next-genera...VEXAS syndrome is an adult-onset autoinflammatory disorder caused by somatic UBA1 variants, but there are no standardized criteria for genetic testing or diagnostics. This study compared Sanger sequencing and next-generation sequencing (NGS) for detecting UBA1 variants in patients with suspected VEXAS, assessed the ability of Sanger sequencing to estimate variant allele fractions (VAFs), and evaluated the Maeda et al. scoring system for selecting patients for genetic testing in a primary cohort and a validation cohort. In the primary cohort of 104 patients, Sanger sequencing identified VEXAS variants in 12%, with no additional cases detected by NGS. Sanger sequencing accurately quantified VAFs ranging from 0.1 to 0.9. In a small longitudinal subset (n = 3), VAFs in blood correlated with CRP levels, increased over time despite various treatments, but decreased in two patients after initiation of Azacitidine treatment. The novel parameters, VAF in myeloid cells and VEXAS cell concentration, showed promise as exploratory markers for patient monitoring. The Maeda-score, requiring a threshold score of 2 for 100% sensitivity, exhibited low specificity-29% in the primary cohort and 41% in the validation cohort (n = 62, with 2 carrying VEXAS variants). In contrast, the simplified SWIM-score-based on Skin involvement, Weight loss, Inflammation, and Macrocytic anemia-achieved 100% sensitivity in both cohorts, with higher specificities of 47% and 65%, respectively. In conclusion, Sanger sequencing reliably detected UBA1 variants and quantified VAFs. Monitoring VAF and VEXAS cell concentration may track disease progression, and the SWIM-score demonstrated potential for accurately selecting patients for UBA1 testing.
Juliana NM, Severs M, Marsden JW
… +6 more, van Montfrans JM, Ellerbroek PM, Lacle MM, Dalm VASH, Abelmoumen A, Leavis HL
J Clin Immunol
· 2025 Sep · PMID 41026260
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PURPOSE: Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and i...PURPOSE: Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and investigated the effectiveness of immunosuppressive treatments on its clinical course. METHOD: We identified patients with CVID-E in two academic teaching hospitals and obtained informed consents. Using electronic patient health care records, we retrospectively collected clinical information in the national Primary immunodeficiency disorder database until 01-2023. RESULTS: We included 39 patients with CVID-E. Bronchiectasis (69.2%) and lymphoproliferation (46.1%) were the most frequent co-occurring symptoms. The most common endoscopy findings concerned inflammation (72.2%) and erythema (69.4%); The most prevalent histopathologic findings were IBD-like inflammation (55.6%), indiscriminate chronic inflammation (47.2%) and indiscriminate active inflammation (38.9%). We assessed 88 events of treatment response in the 25 treated patients. Overall treatment response was poor, however there were 31 events of remission observed, ranging from partial to sustained remission. Of these 26 were the result of tumor necrosis factor inhibitors (TNFi) or thiopurines, either as monotherapy or in combination with other immunosuppressive treatment. 10 patients achieved complete remission. CONCLUSION: In this study, we describe a cohort of CVID-E patients including related comorbidity, clinical course and response to therapy. CVID-E patients frequently develop other, sometimes severe comorbidities. Our study confirms the alleged heterogeneity regarding endoscopic and histopathological findings, and in one third of patients even multiple distinct abnormalities co-occurred in the same biopsy. We found azathioprine and/or TNFi to be the most effective current treatment.